Ontology highlight
ABSTRACT:
PROVIDER: PRJNA889326 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21857700.fastq.gz | Fastqsanger.gz | |||
| SRR21857701.fastq.gz | Fastqsanger.gz | |||
| SRR21857702.fastq.gz | Fastqsanger.gz | |||
| SRR21857703.fastq.gz | Fastqsanger.gz | |||
| SRR21857704.fastq.gz | Fastqsanger.gz |
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Project description:CD8+ tumor-infiltrating lymphocytes with a tissue-resident memory T (TRM) cell phenotype are associated with favorable prognosis in patients with triple negative breast cancer (TNBC). However, the relative contribution of CD8+ TRM cells to anti-tumor immunity and immune checkpoint blockade efficacy in breast cancer remains unknown. Here, we show that intratumoral CD8+ T cells in murine mammary tumors transcriptionally resemble those from triple-negative breast cancer patients. Phenotypic and transcriptional studies established two intratumoral sub-populations: one more enriched in markers of terminal exhaustion (TEX-like) and the other with a bona-fide resident phenotype (TRM-like). Treatment with anti-PD-1 and anti-CTLA-4 therapy resulted in a expansion of these intratumoral populations, with the TRM-like subset displaying significantly enhanced cytotoxic capacity. Importantly, we demonstrate that it is the TRM-like CD8+ T cells can provide local immune protection against mammary tumor re-challenge and that a gene signature from remaining TRM-like CD8+ T cells extracted from tumor-free tissue was significantly associated with improved outcomes in human TNBC patients treated with checkpoint inhibition. Overall, our data suggest that CD8+ T cells with a tissue resident phenotype play a critical role in response to local immunosurveillance and responses to immune checkpoint blockade in breast cancer
2022-12-14 | GSE218161 | GEO
Project description:Analyses of healthy tissue reveal signatures that identify resident memory CD8+ T cells (TRM), which survey tissues without recirculating. The density of TRM-phenotype cells within solid tumors correlates favorably with prognosis, suggesting that intratumoral residents control cancer. However, residence has not been directly tested and intratumoral TRM-phenotype cells could instead reflect aspects of the microenvironment that correlate with prognosis. Using a breast cancer model, we found that conventional TRM markers do not inform the tumor residence of either bystander or tumor-specific cells, which exhibit further distinct phenotypes in the tumor microenvironment and healthy mammary tissue. Rather, tumor-specific, stem-progenitor CD8+ T cells migrate to tumors and become resident while acquiring select markers of exhaustion. These data indicate that tonic antigen stimulation and the tumor environment drive distinct programs of residence compared to healthy tissues and that tumor immunity is sustained by continued migration of tumor-specific stem cells.
2023-06-02 | GSE231541 | GEO
Project description:<p>Plasmacytoid dendritic cells (pDC) are a subset of dendritic cells with unique immunophenotypic properties and functions. While their role in antiviral immunity through production of type I interferons is well-established, their contributions to anti-tumor immunity are less clear. While some evidence demonstrates that pDC in the tumor microenvironment (TME) may drive CD4+ T cell to become <a href="https://www.ncbi.nlm.nih.gov/gene/50943">Foxp3</a>+ T regulatory cells, little is understood about the relationship of pDC with cytotoxic CD8+ T cell, the key player in antitumor immune responses.</p> <p>In this study, we perform comprehensive immunophenotyping and functional analysis of pDC from the TME and draining lymph nodes of patients with head and neck squamous cell carcinoma (HNSCC) and identify a novel pDC subset characterized by expression of the TNF receptor superfamily member <a href="https://www.ncbi.nlm.nih.gov/gene/?term=7293">CD134 (OX40)</a>. We show that OX40 expression is expressed on intratumoral pDC in both humans and mice in a tumor-model specific fashion and that this subset of pDC enhances tumor associated-antigen (TAA)-specific CD8+ T cell responses. Through transcriptomic profiling of OX40-expressing pDC from the TME, we further characterize gene signatures unique to this pDC subset that support its role as an important immunostimulatory immune population in the TME.</p>
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Project description:Identifying new immune checkpoint molecules hindering antitumor T cell responses and devising new therapeutic blockades are key to the development of next-generation cancer immunotherapies. Here, we report the induction of the serotonin transporter (SERT) in solid tumor-infiltrating cytotoxic CD8 T cells, a molecule best known for its role in regulating serotonin neurotransmission in the brain. In solid tumors, CD8 T cells secrete serotonin, which stimulates their antitumor reactivities, while SERT functions as a negative regulator by depleting intratumoral serotonin. Inhibition of SERT using clinically approved selective serotonin reuptake inhibitors (SSRIs), a popular class of antidepressants, significantly suppressed tumor growth and enhanced CD8 T cell-mediated antitumor responses in various preclinical mouse syngeneic and human xenograft tumor models. Importantly, SSRI treatment exhibited significant therapeutic synergy with anti-PD-1 therapy, and clinical data correlation studies negatively associated intratumoral SERT expression with patient survival in a range of cancers. These findings highlight the significance of the intratumoral serotonin axis and identify SERT as a novel immune checkpoint, positioning SSRIs as promising candidates for next-generation combination cancer therapies.
2025-05-27 | GSE262781 | GEO
Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with
advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8
T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.
2023-06-16 | MSV000092193 | MassIVE
Project description:Through a diversity of functional lineages, cells of the innate and adaptive immune system either drive or constrain immune reactions within tumors. Thus, while the immune system has a powerful ability to recognize and kill cancer cells, this function is often suppressed preventing clearance of disease. The transcription factor (TF) BACH2 controls the differentiation and function of multiple innate and adaptive immune lineages, but its role in regulating tumor immunity is not known. Here, we demonstrate that BACH2 is required to establish immunosuppression within tumors. We found that growth of subcutaneously implanted tumors was markedly impaired in Bach2-deficient mice and coincided with intratumoral activation of both innate and adaptive immunity but was dependent upon adaptive immunity. Analysis of tumor-infiltrating lymphocytes in Bach2-deficient mice revealed high frequencies of CD4+ and CD8+ effector cells expressing the inflammatory cytokine IFN-γ. Lymphocyte activation coincided with reduction in the frequency of intratumoral CD4+ Foxp3+ regulatory T (Treg) cells. Mechanistically, Treg-dependent inhibition of CD8+ T cells was required for BACH2-mediated tumor immunosuppression. These findings demonstrate that BACH2 is a key component of the molecular programme of tumor immunosuppression and identify a new target for development of therapies aimed at reversing immunosuppression in cancer. Analysis of tumor-infiltrating lymphocytes in Bach2-deficient mice revealed high frequencies of CD4+ and CD8+ effector cells expressing the inflammatory cytokine IFN-γ. Lymphocyte activation coincided with reduction in the frequency of intratumoral CD4+ Foxp3+ regulatory T (Treg) cells. Mechanistically, Treg-dependent inhibition of CD8+ T cells was required for BACH2-mediated tumor immunosuppression.
2016-06-01 | E-GEOD-74653 | biostudies-arrayexpress
Project description:Coagulation protease signaling within the tumor-microenvironment (TME) causes cancer immune evasion and impairs immune checkpoint-inhibitor therapy. Tumor-associated macrophages produce factor X and drive immune-evasive protease activated receptor-2 (PAR2) signaling. Myeloid FXa-PAR2 signaling promotes the enrichment of resident-like macrophages displaying an immunosuppressive repair phenotype within the TME of mice with genetically induced spontaneous breast cancer development. Conversely, loss of FXa-PAR2 signaling favors the expansion of monocyte-derived macrophage subsets relevant for DNA-sensing, autophagy and cGAS-STING-IFNβ mediated stimulation of anti-tumor immunity. Thereby FXa suppresses the function of CD103+ dendritic cells relevant for priming, reactivation, and expansion of CD8+ T-cells, including antigen-experienced progenitor exhausted T-cells. Our findings thus emphasize the translational potential of FXa inhibition to synergize with immunotherapy.ompacted abstract
2025-07-09 | GSE214518 | GEO
Project description:D2C7-immunotoxin (IT), a dual-specific IT targeting wild-type epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII) proteins, demonstrates encouraging survival outcomes in a subset of patients with glioblastoma. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. To improve the response rate and reverse immunosuppression, we combined D2C7-IT tumor cell killing with αCD40 costimulation of antigen-presenting cells. In murine glioma models, a single intratumoral injection of D2C7-IT+αCD40 treatment activated a proinflammatory phenotype in microglia and macrophages, promoted long-term tumor-specific CD8+ T cell immunity, and generated cures. D2C7-IT+αCD40 treatment increased intratumoral Slamf6+CD8+ T cells with a progenitor phenotype and decreased terminally exhausted CD8+ T cells. D2C7-IT+αCD40 treatment stimulated intratumoral CD8+ T cell proliferation and generated cures in glioma-bearing mice despite FTY720-induced peripheral T cell sequestration. Tumor transcriptome profiling established CD40 upregulation, pattern recognition receptor, cell senescence, and immune response pathway activation as the drivers of D2C7-IT+αCD40 antitumor responses. In order to determine potential translation, immunohistochemistry staining confirmed CD40 expression in human GBM tissue sections. These promising preclinical data allowed us to initiate a phase I study with D2C7-IT+αhCD40 in patients with malignant glioma (NCT04547777) to further evaluate this treatment in humans.
2023-02-17 | GSE221376 | GEO
Project description:This data is from a murine model established to study the lasting impact of allergic airway sensitization on subsequent anti-viral memory T cell responses and the ability to develop protective immunity to reinfection. Animals were either sensitised by exposure to HDM or PBS and then subsequently exposed to influenza virus. Samples were collected at various time points for analysis of both CD8 and C4 positive tissue resident memory T cells.
2023-01-30 | E-MTAB-11116 | biostudies-arrayexpress
Project description:Cancer cells evade T-cell-mediated killing through poorly understood mechanisms of tumour–immune interactions. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1), mediate T-cell priming and therapeutic efficacy against tumours. Besides pattern recognition receptors (PRRs), how DC functions are shaped by other environmental cues remains incompletely defined. Nutrients are emerging mediators of adaptive immunity, but whether nutrients impact DC function or innate–adaptive cell communication is largely unresolved. Here, we establish glutamine as an intercellular metabolic checkpoint to mediate tumour–cDC1 crosstalk and license cDC1 functionality for activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8+ T-cell immunity, and also overcomes therapeutic resistance to checkpoint blockade and T-cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1 compete for glutamine uptake via transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid for promoting cDC1 function, by signalling via FLCN to impinge upon TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner, and phenocopies SLC38A2 deficiency by abrogating anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1 that underpins tumour immunoevasion, and reveal glutamine acquisition and signalling in cDC1 as limiting events for DC activation and putative targets for cancer treatment.
2023-05-24 | GSE210153 | GEO